Genetic Variant HLA-DRB1:c.652+3G>A (chr6-32581554-C-T) – ACMG Classification: Benign (-10 pts)

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_StrongBP6_ModerateBS2

The NM_002124.4(HLA-DRB1):c.652+3G>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.00010 ( 0 hom., cov: 10)

Exomes 𝑓: 0.00049 ( 6 hom. )

Consequence

HLA-DRB1
NM_002124.4 splice_region, intron

Scores

Splicing: ADA: 0.00001678

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: 0.828

Publications

11 publications found

Variant links:

Genes affected

HLA-DRB1 (HGNC:4948): (major histocompatibility complex, class II, DR beta 1) HLA-DRB1 belongs to the HLA class II beta chain paralogs. The class II molecule is a heterodimer consisting of an alpha (DRA) and a beta chain (DRB), both anchored in the membrane. It plays a central role in the immune system by presenting peptides derived from extracellular proteins. Class II molecules are expressed in antigen presenting cells. The beta chain is approximately 26-28 kDa. It is encoded by 6 exons. Exon one encodes the leader peptide; exons 2 and 3 encode the two extracellular domains; exon 4 encodes the transmembrane domain; and exon 5 encodes the cytoplasmic tail. Within the DR molecule the beta chain contains all the polymorphisms specifying the peptide binding specificities. Hundreds of DRB1 alleles have been described and some alleles have increased frequencies associated with certain diseases or conditions. For example, DRB1*1302 has been related to acute and chronic hepatitis B virus persistence. There are multiple pseudogenes of this gene. [provided by RefSeq, Jul 2020]

HLA-DRB1 Gene-Disease associations (from GenCC):

systemic lupus erythematosus
Inheritance: Unknown Classification: SUPPORTIVE Submitted by: Orphanet

HLA-DRB1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -10 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.62).

BP6

Variant 6-32581554-C-T is Benign according to our data. Variant chr6-32581554-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 2656459.Status of the report is criteria_provided_single_submitter, 1 stars.

BS2

High Homozygotes in GnomAdExome4 at 6 Unknown gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002124.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HLA-DRB1	NM_002124.4	MANE Select	c.652+3G>A		splice_region intron	N/A	NP_002115.2	P01911

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
HLA-DRB1	ENST00000360004.6	TSL:6 MANE Select	c.652+3G>A	splice_region intron	N/A	ENSP00000353099.5	P01911
HLA-DRB1	ENST00000963203.1		c.730+3G>A	splice_region intron	N/A	ENSP00000633262.1
HLA-DRB1	ENST00000859900.1		c.652+3G>A	splice_region intron	N/A	ENSP00000529959.1

Frequencies

GnomAD3 genomes

AF:

0.000103

AC:

AN:

77540

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000235

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000157

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000419

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000269

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00333

AC:

597

AN:

179480

AF XY:

0.00329

show subpopulations

Gnomad AFR exome

AF:

0.00355

Gnomad AMR exome

AF:

0.00303

Gnomad ASJ exome

AF:

0.00170

Gnomad EAS exome

AF:

0.00326

Gnomad FIN exome

AF:

0.00299

Gnomad NFE exome

AF:

0.00217

Gnomad OTH exome

AF:

0.00424

GnomAD4 exome

AF:

0.000491

AC:

492

AN:

1001462

Hom.:

Cov.:

AF XY:

0.000622

AC XY:

315

AN XY:

506456

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.000473

AC:

AN:

25362

American (AMR)

AF:

0.00110

AC:

AN:

36236

Ashkenazi Jewish (ASJ)

AF:

0.000794

AC:

AN:

18886

East Asian (EAS)

AF:

0.000253

AC:

AN:

31582

South Asian (SAS)

AF:

0.00336

AC:

227

AN:

67496

European-Finnish (FIN)

AF:

0.000326

AC:

AN:

39936

Middle Eastern (MID)

AF:

0.000733

AC:

AN:

4094

European-Non Finnish (NFE)

AF:

0.000210

AC:

154

AN:

735054

Other (OTH)

AF:

0.000467

AC:

AN:

42816

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.318

Heterozygous variant carriers

104

138

173

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000103

AC:

AN:

77616

Hom.:

Cov.:

AF XY:

0.000188

AC XY:

AN XY:

37288

show subpopulations

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.000234

AC:

AN:

21328

American (AMR)

AF:

0.000157

AC:

AN:

6370

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

1668

East Asian (EAS)

AF:

0.00

AC:

AN:

2732

South Asian (SAS)

AF:

0.000421

AC:

AN:

2374

European-Finnish (FIN)

AF:

0.00

AC:

AN:

4458

Middle Eastern (MID)

AF:

0.00

AC:

AN:

128

European-Non Finnish (NFE)

AF:

0.0000269

AC:

AN:

37158

Other (OTH)

AF:

0.00

AC:

AN:

924

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.250

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00275

Hom.:

ClinVar

ClinVar submissions as Germline

Significance:Likely benign

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.62

CADD

Benign

(source)

DANN

Benign

0.55

PhyloP100

0.83

Mutation Taster

=44/56

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000017

dbscSNV1_RF

Benign

0.024

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over